EP0458929B1 - SOLUBILISATION DE t-PA - Google Patents

SOLUBILISATION DE t-PA Download PDF

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Publication number
EP0458929B1
EP0458929B1 EP91900785A EP91900785A EP0458929B1 EP 0458929 B1 EP0458929 B1 EP 0458929B1 EP 91900785 A EP91900785 A EP 91900785A EP 91900785 A EP91900785 A EP 91900785A EP 0458929 B1 EP0458929 B1 EP 0458929B1
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EP
European Patent Office
Prior art keywords
activity
pharmaceutical preparation
preparation according
protein
glycosylated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP91900785A
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German (de)
English (en)
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EP0458929A1 (fr
Inventor
Ulrich Dr. Kohnert
Rudolph Dr. Rainer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
Boehringer Mannheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical Roche Diagnostics GmbH
Priority to AT91900785T priority Critical patent/ATE102046T1/de
Publication of EP0458929A1 publication Critical patent/EP0458929A1/fr
Application granted granted Critical
Publication of EP0458929B1 publication Critical patent/EP0458929B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • t-PA human tissue plasminogen activator
  • Natural t-PA is composed of several functional domains F, G, K1, K2 and P.
  • Domain P contains the proteolytically active center, which causes the cleavage of plasminogen to plasmin.
  • the genetic engineering of t-PA or various t-PA muteins, in which some of the domains F, G, K1 and K2 have been deleted, in eukaryotic and prokaryotic cells is already known.
  • t-PA derivatives are synthesized from prokaryotes in non-glycosylated form.
  • Proteins with t-PA activity only dissolve in a low concentration in the buffers usually used for solubilizing proteins, such as 50 mmol / l Na citrate, 50 mmol / l phosphate or physiological NaCl solution.
  • proteins with t-PA activity with a higher enzymatic activity of at least 0.25 MU / ml, preferably 0.25 MU / ml to 10 MU / ml, should be present.
  • US Patent 4,777,043 discloses a pharmaceutical composition with human t-PA and a pharmaceutically acceptable buffer containing argininium ions with a chloride ion concentration of up to 0.3 mol / l.
  • EP-A 0 156 169, EP-A 0 303 351 and EP-A 0 297 294 disclose further possibilities for solubilizing proteins with t-PA activity in buffers by amino acids, their salts, derivatives and homologues.
  • t-PA can be stabilized by adding gelatin according to EP-A 0 123 304, by adding albumin according to EP-A 0 112 940 or by adding a poly-sulfuric acid ester of a saccharide or a sulfated sugar according to EP-A 0 198 321.
  • PCT / US88 / 04402 discloses a method for increasing the t-PA solubility, in which an aqueous medium with a basic amino acid, in particular arginine, in a concentration of 0.02 to 0.2 mol / l together with a citric acid group in a concentration of 0.02 to 0.08 mol / l at a pH of 5 to 8 is used.
  • EP-A-0 211 592 discloses a sterile pharmaceutical dosage unit of t-PA for parenteral administration which contains 0.1-15 mg / ml t-PA in a pharmaceutically acceptable buffered aqueous solution at pH 3.5-5.5 .
  • This document describes preparations with a concentration of 0.5 mg / ml glycosylated t-PA in 100 mmol / l citric acid / sodium citrate, pH 5.5.
  • no t-PA muteins or non-glycosylated t-PA are disclosed in EP-A-0 211 592.
  • compositions are not generally suitable for all proteins with t-PA properties.
  • non-glycosylated t-PA, non-glycosylated t-PA muteins and glycosylated t-PA have widely differing solution properties.
  • the object of the invention was therefore to develop pharmaceutical preparations that are glycosylated and not contain glycosylated t-PA or t-PA muteins with an activity of more than 0.25 MU / ml, the t-PA should be stable over a longer period of time.
  • the object of the invention is achieved by a pharmaceutical preparation of a protein with t-PA activity in a concentration of at least 0.4 MU / ml with a pH of 4.5 to 9, this composition being a substance from the group citric acid, Contains ascorbic acid, 2-oxoglutaric acid, fumaric acid, Tris and EDTA in a concentration of at least 0.2 mol / l.
  • a concentration of the abovementioned substances of 0.2 to 1 mol / l is preferred, particularly preferably 0.3 to 1 mol / l.
  • a pH between 4.5 and 9 is suitable for a composition according to the invention, and a pH of 6 to 7.5 is particularly preferred.
  • Protein with t-PA activity means unmodified t-PA from prokaryotic and eukaryotic organisms, as well as all t-PA muteins.
  • t-PA muteins are e.g. in Harris (Protein Engineering 1 (1987), 449-458).
  • composition according to the invention preferably contains native glycosylated t-PA, for example from CHO cells. If a preparation according to the invention contains a native glycosylated t-PA, then its enzymatic activity should preferably be at least 1.4 MU / ml.
  • the unit U is a unit of activity for t-PA as defined by the WHO, National Institute for Biological Standards and Control.
  • t-PA pro A non-glycosylated t-PA from prokaryotes (t-PA pro), which is obtainable according to DE-35 37 708, is also preferred. Under t-PA pro one understands a t-PA starting with the amino acids -3 (Gly) to +1 (Ser) and ending at 527 (Pro) (nomenclature according to Harris, Protein Engineering, Volume 1 (1987) 449- 458). If a preparation according to the invention contains t-PA pro, then its enzymatic activity should be at least 0.25 MU / ml.
  • K1K2P pro A non-glycosylated t-PA mutein with the domains K1, K2 and P, which is referred to as K1K2P pro, is also preferred (production according to DE 39 233 391.1).
  • K1K2P pro starts at amino acid 85-92 and ends at 527 (Pro). If a preparation according to the invention contains K1K2P pro, then its enzymatic activity should preferably be at least 0.4 MU / ml.
  • K2P pro production according to EP-A 0 382 174
  • K2P pro starts at amino acid 174-179 and ends at 527 (Pro).
  • K2P pro as well as K1K2P pro can contain part or all of the amino acids -3 (Gly) to +5 (Ile) according to Harris, supra.
  • a preparation according to the invention contains K2P pro, then its enzymatic activity should preferably be at least 1.4 MU / ml.
  • all other t-PA variants made from prokaryotes or eukaryotes are also suitable.
  • One formulation contains 300 mmol / l citric acid / NaOH, pH 6.
  • Another formulation contains 300 mmol / l ascorbic acid, pH 6.
  • another formulation contains 300 mmol / l 2-oxoglutaric acid, pH 6.
  • Another formulation contains 300 mmol / l EDTA, pH 6.
  • Another formulation contains 300 mmol / l fumaric acid / NaOH, pH 6.
  • Another formulation contains 1 mol / l Tris / HCl, pH 7.2.
  • the invention also relates to a medicament based on a protein with t-PA activity as an active ingredient in solution or as a lyophilisate with the specified active ingredients and optionally other pharmaceutically acceptable additives, auxiliaries, carriers and fillers.
  • the pharmaceutical preparations according to the invention are preferably used as injection and infusion solutions. This can be done by providing an already ready-to-use solution which has the composition according to the invention. However, it is also possible to provide the pharmaceutical preparations in the form of lyophilisates. These are then reconstituted with means or solutions known per se which are suitable for injection purposes. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers, buffers and isotonic additives, for example a physiological NaCl concentration.
  • Such additives are, for example, mannitol, tartrate or citrate buffers, ethanol, complexing agents such as, for example, ethylenediaminetetraacetic acid and its non-toxic salts, and high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation.
  • Liquid Carriers for injection solutions must be sterile and are preferably filled into ampoules.
  • the present invention also includes the use of glycosylated proteins with t-PA activity for the production of pharmaceutical preparations according to the invention.
  • K2P pro dissolves in the buffer solutions listed with a significantly higher activity than 1.4 MU / ml.
  • the enzymatic activity is given as volume activity in MU / ml and as total activity in MU.
  • t-PA activity can be determined in the usual way by cleaving a chromogenic substrate (H. Lill, ZGIMAL 42, (1987), 478-486).
  • the unit U is a unit of activity for t-PA as defined by the WHO, National Institute for Biological Standards and Control.
  • Purified K1K2P pro (dissolved in 0.5 mol / l arginine / H3PO4) is concentrated by ultrafiltration over a YM 10 membrane (Amicon). 0.5 ml portions of the concentrate (activity: 3.5 MU / ml) are dialyzed against the buffers listed in Table 2. After centrifugation of the samples, the enzymatic activity is measured in the clear supernatant.
  • the enzymatic activity is given as a volume unit in MU / ml and as a total activity in MU.
  • the measurement of tPA activity can be determined in the usual way by cleaving a chromogenic substrate (H. Lill, ZGIMAL 42 (1987), 478-486).
  • the unit U is a unit of activity as defined by the WHO, National Institute for Biological Standards and Control.
  • Purified tPA pro (dissolved in 0.5 mol / l arginine / H3PO4) is by ultrafiltration over a YM 10 membrane (Amicon) focused. 1 ml of the concentrate (activity: 2.4 MU / ml) is dialyzed against the buffers listed in Table 3. After centrifugation of the samples, the enzymatic activity is measured in the clear supernatant.
  • the enzymatic activity is given as a volume unit in MU / ml and as a total activity in MU.
  • the measurement of tPA activity can be determined in the usual way by cleaving a chromogenic substrate (H. Lill, ZGIMAL 42 (1987), 478-486).
  • the unit U is a unit of activity as defined by the WHO, National Institute for Biological Standards and Control.
  • CHO-tPA dissolved in 0.5 mol / l arginine / H3PO4 is concentrated by ultrafiltration over a YM 10 membrane (Amicon). 1 ml of the concentrate (activity: 6.6 MU / ml) is dialyzed against the buffers listed in Table 4. After centrifugation of the samples, the enzymatic activity is measured in the clear supernatant.
  • the enzymatic activity is given as a volume unit in MU / ml and as a total activity in MU.
  • the measurement of tPA activity can be determined in the usual way by cleaving a chromogenic substrate (H. Lill, ZGIMAL 42, (1987), 478-486).
  • the unit U is a unit of activity as defined by the WHO, National Institute for Biological Standards and Control.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Saccharide Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
  • Oscillators With Electromechanical Resonators (AREA)
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Claims (17)

  1. Préparation pharmaceutique d'une protéine présentant l'activité du t-PA et ayant une activité enzymatique d'au moins 0,25 MU/ml et un pH de 4,5 à 9, caractérisée en ce qu'elle contient une substance du groupe de l'acide citrique, de l'acide ascorbique, de l'acide 2-oxoglutarique, de l'acide fumarique, du Tris et de l'EDTA en une concentration d'au moins 0,2 mol/l.
  2. Préparation pharmaceutique selon la revendication 1, caractérisée en ce que la concentration des substances citées ci-dessus est de 0,2 à 1 mol/l.
  3. Préparation pharmaceutique selon la revendication 1, caractérisée en ce que la concentration des substances citées ci-dessus est de 0,3 à 1 mol/l.
  4. Préparation pharmaceutique selon l'une des revendications 1 à 3, caractérisée en ce que la protéine présentant l'activité du t-PA possède la composition de domaines K2P, n'est pas glycosylée et possède une activité enzymatique d'au moins 1,4 MU/ml.
  5. Préparation pharmaceutique selon l'une des revendications 1 à 3, caractérisée en ce que la protéine présentant l'activité du t-PA possède la composition de domaines K1K2P, n'est pas glycosylée et possède une activité enzymatique d'au moins 0,4 MU/ml.
  6. Préparation pharmaceutique selon l'une des revendications 1 à 3, caractérisée en ce que la protéine présentant l'activité du t-PA est un t-PA pro non glycosylé et possède une activité enzymatique d'au moins 0,25 MU/ml.
  7. Préparation pharmaceutique selon l'une des revendications 1 à 3, caractérisée en ce que la protéine présentant l'activité du t-PA est un t-PA glycosylé possédant une activité enzymatique d'au moins 1,4 MU/ml.
  8. Préparation pharmaceutique selon l'une des revendications précédentes, caractérisée en ce qu'elle contient 300 mmol/l d'acide citrique/NaOH, pH 6.
  9. Préparation pharmaceutique selon l'une des revendications précédentes, caractérisée en ce qu'elle contient 300 mmol/l d'acide ascorbique/NaOH, pH 6.
  10. Préparation pharmaceutique selon l'une des revendications précédentes, caractérisée en ce qu'elle contient 300 mmol/l d'acide 2-oxoglutarique/NaOH, pH 6.
  11. Préparation pharmaceutique selon l'une des revendications précédentes, caractérisée en ce qu'elle contient 300 mmol/l d'EDTA/NaOH, pH 6.
  12. Préparation pharmaceutique selon l'une des revendications précédentes, caractérisée en ce qu'elle contient 300 mmol/l d'acide fumarique/NaOH, pH 6.
  13. Préparation pharmaceutique selon l'une des revendications précédentes, caractérisée en ce qu'elle contient 1 mol/l de Tris/HCl, pH 7,2.
  14. Préparation pharmaceutique à base d'une protéine présentant l'activité du t-PA en tant que principe actif, caractérisée par une composition selon l'une des revendications précédentes, éventuellement avec des additifs, adjuvants et/ou véhicules pharmaceutiques habituels.
  15. Procédé d'obtention d'une préparation pharmaceutique selon l'une des revendications 1 à 14, caractérisé en ce que l'on convertit en une forme d'administration pharmaceutique appropriée une protéine présentant l'activité du t-PA conjointement avec une substance du groupe selon la revendication 1.
  16. Procédé selon la revendication 15, caractérisé en ce que la forme d'administration pharmaceutique est une solution pour injection ou un lyophilisat.
  17. Utilisation d'une protéine présentant l'activité du t-PA pour l'obtention de préparations pharmaceutiques selon l'une des revendications 1 à 14.
EP91900785A 1989-12-20 1991-07-12 SOLUBILISATION DE t-PA Expired - Lifetime EP0458929B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT91900785T ATE102046T1 (de) 1989-12-20 1991-07-12 T-pa-solubilisierung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3942145 1989-12-20
DE3942145A DE3942145A1 (de) 1989-12-20 1989-12-20 T-pa-solubilisierung

Publications (2)

Publication Number Publication Date
EP0458929A1 EP0458929A1 (fr) 1991-12-04
EP0458929B1 true EP0458929B1 (fr) 1994-03-02

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ID=6395928

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91900785A Expired - Lifetime EP0458929B1 (fr) 1989-12-20 1991-07-12 SOLUBILISATION DE t-PA

Country Status (11)

Country Link
EP (1) EP0458929B1 (fr)
JP (1) JPH0657660B2 (fr)
KR (1) KR920700683A (fr)
AT (1) ATE102046T1 (fr)
AU (1) AU625831B2 (fr)
CA (1) CA2046598C (fr)
DE (2) DE3942145A1 (fr)
FI (1) FI95998C (fr)
HU (2) HU208630B (fr)
NO (1) NO305582B1 (fr)
WO (1) WO1991008764A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3942141A1 (de) * 1989-12-20 1991-06-27 Boehringer Mannheim Gmbh K2p pro-stabilisierung
US7658721B2 (en) 2004-01-16 2010-02-09 Biodel Inc. Sublingual drug delivery device
US20080090753A1 (en) 2004-03-12 2008-04-17 Biodel, Inc. Rapid Acting Injectable Insulin Compositions
US9060927B2 (en) 2009-03-03 2015-06-23 Biodel Inc. Insulin formulations for rapid uptake

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZW14486A1 (en) * 1985-07-29 1986-10-22 Smithkline Beckman Corp Pharmaceutical dosage unit
US4777043A (en) * 1985-12-17 1988-10-11 Genentech, Inc. Stabilized human tissue plasminogen activator compositions
GB8612868D0 (en) * 1986-05-27 1986-07-02 Mars G B Ltd Beverage packages
US4830853A (en) * 1986-10-20 1989-05-16 Warner-Lambert Company Drug compositions stabilized against oxidation
US4898826A (en) * 1987-12-10 1990-02-06 Invitron Corporation Method to solubilize tissue plasminogen activator
US4980165A (en) * 1989-01-27 1990-12-25 Genetics Institute, Inc. Pharmaceutical formulations of plasminogen activator proteins
DE3942142A1 (de) * 1989-12-20 1991-06-27 Boehringer Mannheim Gmbh Stabilisierung von glykosyliertem t-pa

Also Published As

Publication number Publication date
JPH0657660B2 (ja) 1994-08-03
WO1991008764A1 (fr) 1991-06-27
ATE102046T1 (de) 1994-03-15
AU6914991A (en) 1991-07-18
DE3942145A1 (de) 1991-06-27
HUT60133A (en) 1992-08-28
KR920700683A (ko) 1992-08-10
CA2046598C (fr) 1997-01-14
NO912775D0 (no) 1991-07-15
AU625831B2 (en) 1992-07-16
JPH04503680A (ja) 1992-07-02
HU208630B (en) 1993-12-28
NO912775L (no) 1991-07-15
CA2046598A1 (fr) 1991-06-21
NO305582B1 (no) 1999-06-28
EP0458929A1 (fr) 1991-12-04
DE59004814D1 (de) 1994-04-07
FI913907A0 (fi) 1991-08-19
FI95998B (fi) 1996-01-15
FI95998C (fi) 1996-04-25
HU912740D0 (en) 1992-01-28

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